Carrier particles for use in dry powder inhalers

ABSTRACT

In a method of producing particles suitable for use as carrier particles in dry powder inhalers, particles ( 1 ) of a size suitable for use as carrier particles in dry powder inhalers are treated so as to dislodge small grains from the surface of the particles, without substantially changing the size of the particles during the treatment. The treatment gives improved efficiency of redispersion of active particles from the surfaces of carrier particles.

This invention relates to carrier particles for use in dry powderinhalers. More particularly the invention relates to a method ofproducing such particles, to a dry powder incorporating the particlesand to the particles themselves.

Inhalers are well known devices for administering pharmaceuticalproducts to the respiratory tract by inhalation. Inhalers are widelyused particularly in the treatment of diseases of the respiratory tract.

There are a number of types of inhaler currently available. The mostwidely used type is a metered dose inhaler (MDI) which uses a propellantto expel droplets containing the pharmaceutical product to therespiratory tract. Those devices are disadvantageous on environmentalgrounds as they use CFC propellants.

An alternative device to the MDI is the dry powder inhaler. The deliveryof dry powder particles of pharmaceutical products to the respiratorytract presents certain problems. The inhaler should deliver the maximumpossible proportion of the active particles expelled to the lungs,including a significant proportion to the lower lung, preferably at thelow inhalation capabilities to which some patients, especiallyasthmatics, are limited. It has been found, however, that, whencurrently available dry powder inhaler devices are used, in many casesonly about 10% of the active particles that leave the device oninhalation are deposited in the lower lung. More efficient dry powderinhalers would give clinical benefits.

The type of dry powder inhaler used is of significant importance to theefficiency of delivery of the active particles to the respiratory tract.Also, the physical properties of the active particles used affect boththe efficiency and reproducibility of delivery of the active particlesand the site of deposition in the respiratory tract.

On exit from the inhaler device, the active particles should form aphysically and chemically stable aerocolloid which remains in suspensionuntil it reaches an alveolar or other absorption site preferably in thelungs. Once at the absorption site, the active particle should becapable of efficient collection by the pulmonary mucosa with no activeparticles being exhaled from the absorption site.

The size of the active particles is particularly important. Foreffective delivery of active particles deep into the lungs, the activeparticles should be small, with an equivalent aerodynamic diametersubstantially in the range of 1 to 5 μm, approximately spherical andmonodispersed in the respiratory tract. Small particles are, however,thermodynamically unstable due to their high surface area to volumeratio, which provides significant excess surface free energy andencourages particles to agglomerate. In the inhaler, agglomeration ofsmall particles and adherence of particles to the walls of the inhalerare problems that result in the active particles leaving the inhaler aslarge agglomerates or being unable to leave the inhaler and remainingadhered to the interior of the inhaler.

The uncertainty as to the extent of agglomeration of the particlesbetween each actuation of the inhaler and also between differentinhalers and different batches of particles, leads to poor dosereproducibility. It has been found that powders are reproduciblyfluidisable, and therefore reliably removable from an inhaler device,when the particles have a diameter greater than 90 μm.

To give the most effective dry powder aerosol, therefore, the particlesshould be large while in the inhaler, but small when in the respiratorytract.

In an attempt to achieve that situation, one type of dry powder for usein dry powder inhalers may include carrier particles to which the fineactive particles adhere whilst in the inhaler device, but which aredispersed from the surfaces of the carrier particles on inhalation intothe respiratory tract to give a fine suspension. The carrier particlesare often large particles greater than 90 μm in diameter to give goodflow properties as indicated above. Small particles with a diameter ofless than 10 μm may become coated on the wall of the delivery device andhave poor flow and entrainment properties leading to poor doseuniformity.

The increased efficiency of redispersion of the fine active particlesfrom the agglomerates or from the surfaces of carrier particles duringinhalation is regarded as a critical step in improving the efficiency ofthe dry powder inhalers.

It is known that the surface properties of a carrier particle areimportant. The shape and texture of the carrier particle should be suchas to give sufficient adhesion force to hold the active particles to thesurface of the carrier particle during fabrication of the dry powder andin the delivery device before use, but that force of adhesion should below enough to allow the dispersion of the active particles in therespiratory tract.

It is an object of the invention to provide a method of producingcarrier particles for use in dry powder inhalers and to provide carrierparticles that overcome or mitigate the problems referred to above.

According to the invention there is provided a method of producingparticles suitable for use as carrier particles in dry powder inhalers,the method including the step of treating particles of a size suitablefor use as carrier particles in dry powder inhalers to dislodge smallgrains from the surfaces of the particles, without substantiallychanging the size of the particles during the treatment.

The surface of the carrier particle is not smooth but has asperities andclefts in the surface. The site of a cleft or an asperity is often foundto be an area of high surface energy. The active particles arepreferentially attracted to and adhere most strongly to those highenergy sites causing uneven and reduced deposition of the activeparticles on the carrier surface. If an active particle adheres to ahigh energy site, it is subjected to a greater adhesion force than aparticle at lower energy sites on the carrier particle and willtherefore be less likely to be able to leave the surface of the carrierparticle and be dispersed in the respiratory tract. During the treatmentasperities are removed as small grains, thus removing active sitesassociated with the asperities.

Advantageously, the small grains become reattached to the surfaces ofthe particles. The object of treating the carrier particles is to reducethe number of high energy sites on the carrier particle surfaces, thusallowing an even deposition of active particles adhered on the surfacewith a force of adhesion such that dispersion of the active particlesduring inhalation is efficient. While removing asperities as smallgrains removes those high energy sites associated with the asperities,the surfaces of the carrier particle have other high energy sites, forexample at the site of clefts, which sites are not necessarily removedwhen the apserities are removed. It would therefore be highlyadvantageous to decrease the number of those high energy sites.

The grains removed from the surface are small and thermodynamicallyunstable and are attracted to and adhere to the high energy sites on thesurface of the carrier particle. On introduction of the activeparticles, many of the high energy sites are already occupied, and theactive particles therefore occupy the lower energy sites on the carrierparticle surfaces. That results in the easier and more efficient releaseof the active particles in the airstream created on inhalation, therebygiving increased deposition of the active particles in the lungs.

Advantageously, the treatment step is a milling step. The millingprocess causes asperities on the surfaces of the carrier particles to bedislodged as small grains. Many of those small grains become reattachedto the surfaces of the carrier particles at areas of high energy.

Preferably, the milling step is performed in a ball mill. Preferably,the carrier particles are milled using plastics or steel balls. Ballsmade of plastics material give less aggressive milling, whilst steelballs confer more efficient surface smoothing. Advantageously, the millis rotated at a speed of less than about 60 revolutions per minute, moreadvantageously at a speed of less than about 20 revolutions per minute,and most preferably at a speed of about six revolutions per minute. Thatis a slow speed for ball milling and results in the gentle removal ofgrains from the surfaces of the particles and little fracture ofparticles. Fracture of the particles, which occurs with aggressivemilling conditions, for example at higher milling speeds such as 60revolutions per minute and/or long milling times, may result inagglomerates of fractured particles of carrier material. The use ofagglomerates of particles as carrier particles has been found to lead togood deposition of active particles in the lower lung.

Advantageously, the particles are milled for at least one hour,preferably the particles are milled for about six hours. That time hasbeen found to be suitable when milling with balls made from plasticsmaterial. When using denser balls, shorter milling times may be used.Alternatively, a different milling technique may be used, for exampleusing a re-circulated low fluid energy mill, or other method thatresults in the removal of grains from the surfaces of the particles e.g.sieving.

The carrier particles may include may acceptable pharmacologically inertmaterial or combination of materials. Advantageously, the carrierparticles are crystalline sugar particles. Preferably, the carrierparticles are lactose particles.

Advantageously, the diameter of the carrier particles lies between 50 μmand 1000 μm. Preferably, the diameter of the carrier particles is lessthan 355 μm and lies between 60 μm and 250 μm, more preferably 90 μm and250 μm. The relatively large diameter of the carrier particle improvesthe opportunity for active particles to become attached to carrierparticles which is controlled by the above technique to provide goodflow and entrainment characteristics and improved release of the activeparticles in the airways to increase deposition of the active particlesin the lower lung.

The size of the carrier particles is an important factor in theefficiency of the inhaler, and an optimum, or near optimum, range ofsize of carrier particles is preferably selected. The optimum range ofsize of carrier particles may differ according to the inhaler device andactive particles used. Thus, the method preferably includes the step ofselecting an advantageous range of size of carrier particles prior tothe treatment step. That step of selecting an advantageous range of sizemay be a sieving step.

According to the invention, there is also provided a method of producinga dry powder for use in dry powder inhalers, the method including thesteps of treating carrier particles to dislodge small grains from thesurfaces of the carrier particles without substantially changing thesize of the carrier particles during the treatment step, and mixing thetreated carrier particles with active particles such that activeparticles adhere to the surfaces of carrier particles.

Advantageously, the small grains become reattached to the surfaces ofthe carrier particles.

Advantageously, the method includes the steps of treating carrierparticles according to the present invention and mixing the treatedcarrier particles with the active particles such that active particlesadhere to the surfaces of carrier particles. The treatment of thecarrier particles may be carried out before the active particles areadded, but it may also be carried out in the presence of the activeparticles.

Advantageously, the carrier particles and the active particles are mixedin a container made from a plastics material. That has been found togive an unstable mixture of salbutamol and lactose and thus increasesthe deposition of salbutamol in the lungs. A container of differentmaterial may be used when using a mixture containing a different type ofactive particles.

Advantageously, the carrier particles and the active particles are mixedfor at least five minutes. Preferably, the carrier particles and theactive particles are mixed for about thirty minutes. The mixing shouldbe for a time sufficient to give a homogeneous mixture of the activeparticles and the carrier particles, during mixing, rearrangement of thesites of particles may also occur, even when the system is homogeneous.

Advantageously, the mixing is interrupted and the mixture of carrierparticles and active particles is sieved. The sieving of the mixturereduces the number of large agglomerates present. Preferably, the sievemesh size is about 250 μm.

The ratio in which the carrier particles and active particles are mixedis dependent on the inhaler device and the active particles used. Forthe example given below, a ratio of 125 to 1 by weight is preferablyused.

Advantageously, the diameter of the active particles is between 0.1 μmand 3 μm such that the particles give a good suspension on redispersionfrom the carrier particles and are delivered deep into the respiratorytract.

The active particles may include a β₂-agonist which may be terbutaline,a salt of terbutaline or a combination thereof or may be salbutamol, asalt of salbutamol or a combination thereof. Salbutamol and its saltsare widely used in the treatment of respiratory disease. The activeparticles may be particles of salbutamol sulphate.

The active particles may include a steroid, which may be beclomethasonedipropionate. The active principle may include a cromone which may besodium cromoglycate. The active principle may include a leukotrienereceptor antagonist.

According to the invention, there are also provided particles suitablefor use as carrier particles in a dry powder inhaler, the particlesconsisting of small grains and large particles to the surfaces of whichthe small grains are attached.

Preferably, the small grains have a diameter between 1 μm and 5 μm and,preferably, the large particles have a diameter between 50 μm and 1000μm.

Preferably, the large particles are particles of lactose.

According to the invention, there are also provided particles suitablefor use as carrier particles in a dry powder inhaler wherein theparticles are made by a method according to the invention.

According to the invention there is further provided a dry powdersuitable for use in a dry powder inhaler including carrier particlesaccording to the invention and active particles, wherein active partiesadhere to the surfaces of carrier particles.

The carrier particles usually consist of a particulate crystallinesugar. Lactose particles are often used as carrier particles.

The active particles referred to throughout the specification will beparticles of one or a mixture of pharmaceutical products. Thosepharmaceutical products include those products which are usuallyadministered orally by inhalation for the treatment of disease such asrespiratory disease eg. β-agonists, salbutamol and its salts. Otherpharmaceutical products which could be administered using a dry powderinhaler include peptides and polypeptides, such as insulin. In additionthe method could find use in nasal delivery.

According to a further aspect of the invention, there is provided amethod of producing particles including the step of treating largeparticles such that small grains adhere to the surfaces of the largeparticles.

As indicated above, the surfaces of the large particles are notcompletely smooth even following treatment such as milling but haveasperities and clefts. As a result, the surfaces have areas of highsurface energy to which active particles are preferentially attached. Anactive particle at a high energy site is less likely to be able to leavethe surface and be dispersed in the respiratory tract than an activeparticle at a site of lower surface energy. During the treatment of thelarge particles, the small grains are attracted to and adhere to highenergy sites on the surface of the large particles. On the introductionof the active particles, many of the high energy sites are alreadyoccupied, and the active particles therefore occupy the lower energysites on the carrier particle surfaces. That results in the easier andmore efficient release of the active particles in the airstream createdon inhalation, thereby giving increased deposition of the activeparticles in the lungs.

Advantageously the step of treating large particles such that smallgrains adhere to the surfaces of the large particles is a mixing step.Small grains, or agglomerates of small grains, may be introduced to asample of large particles which may have been treated to dislodge smallgrains from the surfaces of the particles and the mixture blended forseveral hours to allow the small grains to become attached to thesurfaces of the large particles.

The small grains added to the large particles are preferably the productof milling large particles. If the large particles are subjected toaggressive milling, for example at high milling speed, small grains areproduced. Those small grains may form larger agglomerates.

Advantageously, the large particles and small grains are mixed in aratio by weight of at least one part of large particles to each part ofstall grains. For example, the proportion of small grains may be between10 and 30 per cent, especially of the order of 20 per cent by weightbased on the combined weight of the small grains and the largeparticles. It has been found to be highly advantageous for the surfacesof the large particles to become saturated with small grains. Some ofthe small grains may act as carrier particles for active particles, byleaving the surfaces of the large particles with active particlesattached to their surfaces. The dimensions of the combined activeparticle and small grain are generally still within the optimum valuesfor good deposition in the lower lung. It is believed that activeparticles which adhere to the small grains on the large particles, arepreferentially released from the surface of the large particles.

Embodiments of the invention will now be described by way of examplewith reference to the accompanying drawings, of which:

FIGS. 1 a to c show the effect of a milling treatment on the surface ofa particle,

FIG. 2 is a perspective view of a dry powder inhaler,

FIG. 3 is a sectional diagram of a twin stage impinger.

The following Examples illustrate the invention.

EXAMPLE 1

Carrier particles were prepared by the following method. Meggle lactoseEP D30 (an α lactose monohydrate: pure crystalline milk sugar) was used.Lactose EP D30 has a useful starting particle size range and acceptableflow properties.

-   (a) The lactose was sieved by the following method conforming to    British Standard No. 410 to give samples having particles with a    range of diameter from 90 to 125 μm. Samples of 30 g of Lactose EP    D30 were sieved mechanically for 20 minutes using a stack of woven    wire stainless steel sieves of mesh aperture diameters 90 μm, 125 μm    and 180 μm. The mesh was vibrated at high speed to reduce the    binding of lactose particles to the mesh of the sieve. After ten    minutes of the sieving process, the sieving was stopped and each of    the sieves was dismantled individually and the powder on the sieve    was removed, the sieve brushed and the powder replaced in the sieve    from which it was removed. The sieve stack was then reassembled and    the sieving resumed. This was done in an attempt to improve the    efficiency of the sieving process.    -   50 g samples of the lactose EP D30 were taken from the particles        that had passed through the 125 μm mesh sieve but had remained        on the 90 μm sieve. Those particles could be considered to have        a diameter between 90 μm and 125 μm.-   (b) The samples obtained in step (a) above were milled in a    porcelain ball mill (manufactured by Pascal Engineering Company).    Plastics grinding balls having an approximate diameter of 10 mm were    used and the mill which had a diameter of approximately 150 mm was    revolved at a slow speed of 6 revolutions per minute for six hours.    During the milling process, the mill was periodically stopped and    any powder adhered to the mill wall or to the plastics grinding    balls, was scraped free.-   (c) Small samples of the milled lactose particles were mounted for    scanning electron microscope (SEM) analysis and were sputtered with    gold. The SEM analysis showed the extent of grinding of the lactose    particles and the alteration of the surfaces of the lactose    particles.    -   FIG. 1 a shows a representation of an untreated particle 1        having asperities 2 and clefts 3. FIG. 1 b shows the effect of a        milling treatment on the particle of FIG. 1 a. Shaded areas 4        represent the sections removed from the surface of the particle        as small grains during the milling.    -   In FIG. 1 c small grains 5 have become reattached to the surface        of the particle, mostly at active sites on the surface.-   (d) Samples of the milled lactose particles were mixed with the    active particles. 0.4 g of salbutamol sulphate (mass median diameter    4.6 μm) were added to 50 g of the milled lactose particles in a    plastics container. After blending for ten minutes using an Erweka    AR400 cube blender, the mixture was removed from the container and    screened through a sieve of mesh aperture diameter 250 μm to remove    any large agglomerations of active particles which may have formed.    The mixture was returned to the container and blended for a further    twenty minutes. The mixture was stored in the plastics container for    five days to allow the decay of any accumulated electric charges.    -   The blending process was repeated for a 50 g sample of lactose        particles which had been taken from the sieved sample of        particles of diameter between 90 μm and 125 μm, but which had        not been milled, to give a comparative example.-   (e) After five days, six samples each of 100 mg of mixture were    taken from the container containing the milled carrier particles,    and four samples each of 100 mg were taken from the container    containing the unmilled carrier particles. Each sample was used to    fill a respective one of ten size three capsules (size 3 opaque,    Elanco BN 3D056D). Those capsules were allowed to stand for two days    to allow the decay of any accumulated electric charge.-   (f) In order to assess the effectiveness of the mixing method, ten    100 mg samples were taken randomly from each of the two mixes (and    were made up to 250 ml with distilled water) and were analyzed using    spectrofluorimetry on a Shimadzu RS S40 spectrofluorimeter at an    excitation wavelength of 223 nm and an emission wavelength of 303 nm    as described below. The samples were analyzed against standard    solutions of 1 μg/ml salbutamol sulphate and 5 μg/ml salbutamol    sulphate, and the concentrations of each of the samples were    calculated.    -   The mass of salbutamol in the mix could therefore be calculated        for each of the samples. The coefficient of variation (CV:        calculated as the standard deviation of the values divided by        the mean value×100) of the mass was calculated for the ten        samples of the mixture containing the milled particles and for        the ten samples of the mixture containing the unmilled        particles.    -   Any mixture for which the value for the coefficient of variation        is calculated to be lower than 4.0 is usually regarded as being        a homogeneous mixture. The mixture containing the unmilled        particles gave a CV of 0.7 and the mixture containing the milled        particles gave a CV of 1.3. Thus both mixtures were considered        to be homogeneous.-   (g) The effect of the milling method on the surfaces of the lactose    particles was verified using a dry powder inhaler device and a    pharmacopoeial apparatus, for in vitro assessment of inhaler    performance.-   (g) (i) FIG. 2 shows a view of a dry powder inhaler known as a    Rotahaler. The inhaler comprises an outer cylindrical barrel 11 and    an inner cylindrical barrel 12 of similar radius such that the inner    barrel 12 is just able to fit inside the outer barrel 11. A mesh 13    is attached across an end of the inner barrel 12 and a mouthpiece 14    is attached around that end section of the inner barrel 12. The    outer barrel 11 is closed at one end by an end section 15 which    contains inlet slots 16 and an aperture 17. The inner barrel 12 also    contains a fin 18 along a length of the inner barrel at the open    end, the fin extending radially inwards from the internal surface of    the inner barrel 12.    -   To operate the device, the inner barrel 12 is inserted into the        open end of the outer barrel 11 such that the mouthpiece meets        the outer barrel 11 and the open end of the inner barrel is at        the end section 15. Capsule 19 containing the mixture of carrier        particles and active particles is inserted into the aperture 17        such that a portion of the capsule 19 is held in the end section        15, and a portion of the capsule 19 extends into the inner        barrel 12. The outer barrel 11 is rotated relative to the inner        barrel 12 and thus the fin 18 engages and breaks the capsule. A        patient inhales through the mouthpiece 14, air is drawn into the        Rotahaler through the inlet slots 16, and the contents of the        capsule are discharged into the inner barrel as a cloud of        powder and inhaled via the mouthpiece 14. The mesh 13 prevents        the inhalation of large particles or of the broken capsule.-   (g) (ii) FIG. 3 shows a diagrammatic arrangement of a twin stage    impinger (TSI). The TSI is a two stage separation device used in the    assessment of oral inhalation devices. Stage one of the apparatus is    shown to the right of the line AB in FIG. 3 and is a simulation of    the upper respiratory tract. To the left of that line is stage two    which is a simulation of the lower respiratory tract.    -   The TSI comprises a mouth 21 which comprises a        polydimethylsiloxane adaptor, moulded to accept the mouthpiece        of the inhaler device, upper tubing 22 and upper impinger 23 to        simulate the upper respiratory tract, the upper impinger        containing liquid 24, and lower tubing 25 and lower impinger 26        to simulate the lower respiratory tract, the lower impinger        containing liquid 27. The lower impinger 26 is connected via an        outlet pipe 28 to a pump 29 which draws air through the TSI        apparatus at a predetermined rate. The base of the lower tubing        25 is at the level of the liquid 27 such that all the air drawn        through the TSI bubbles through the lower liquid 27. The liquid        used in both the upper and lower impinger is distilled water.    -   In use, the inhaler is placed in a mouth 21 of the TSI. Air is        caused to flow through the apparatus by means of a pump 29 which        is connected to stage two of the TSI. Air is sucked through the        apparatus from the mouth 21, flows through upper tubing 22 via        the upper impinger 23 and the lower tubing 25 to the lower        impinger 26 where it bubbles through liquid 27 and exits the        apparatus via outlet pipe 28. The liquid 24 in the upper        impinger 23 traps any particle with a size such that it is        unable to reach stage two of the TSI. Fine particles, which are        the particles able to penetrate to the lungs in the respiratory        tract, are able to pass into stage two of the TSI where they        flow into the lower impinger liquid 27.-   (h) 30 ml of distilled water was put into the lower impinger 26 and    7 ml of distilled water was put into the upper impinger 23. The    lower tubing 25 was arranged such that its lower end was at the    level of the water in the lower impinger 26. The pump 29 was    adjusted to give an air flow rate of 60 litres per minute in the    apparatus.    -   The Rotahaler was weighed when empty. One of the prepared        capsules was inserted into aperture 17 and the inhaler was        reweighed. The mouthpiece 14 of the inhaler was connected to the        mouth 21 of the TSI, the outer barrel 11 was rotated to break        the capsule 19 and the pump was switched on and timed for a        period of ten seconds. The pump was then switched off and the        Rotahaler was removed from the TSI, reweighed and the amount of        powder lost from the inhaler calculated.    -   The remaining powder in the inhaler was washed into a flask for        analysis and made up to 100 ml with distilled water. The        sections of the apparatus making up stage one of the TSI were        washed into a second flask and made up to 250 ml with distilled        water. The sections making up the second stage of the TSI were        washed into a third flask and made up to 100 ml with distilled        water.    -   The other capsules were tested in the same way in a        predetermined random order.    -   The contents of the flasks were then analyzed        spectrofluorimetrically using a Shimadzu R5 S40        spectrophotofluorimeter at excitation wavelength 223 nm and        emission wavelength 303 nm. Standard solutions of the active        particles were also analyzed thus enabling the amount of active        particles deposited in each of the stages to be determined.        Salbutamol gives good fluorescence.-   (j) The contents of the flasks containing the washing from the    stages of the TSI were analyzed using the spectrophotofluorimeter at    excitation wavelength 223 nm and emission wavelength of 303 nm. The    scan speed was set at medium and sensitivity high with an excitation    slit width of 10 nm and emission slit width of 10 nm. The relative    emission intensities were measured for each of the salbutamol    solutions.

Standard solutions containing 1 μg/ml and 5 μg/ml of salbutamol sulphatewere made up using distilled water and the spectrofluorimetric analysiswas repeated for each of those two samples.

-   -   Assuming a linear relationship between the intensity of the        emitted fluorescence and the concentration of salbutamol in the        samples, the concentration of salbutamol in the samples taken        from the TSI could be calculated via the known intensities and        concentrations of the standard samples.    -   The percentage of salbutamol in each stage of the TSI could be        calculated for each capsule and the mean for the milled samples        and the unmilled samples could be calculated.

-   (k) Table 1 below shows the relative intensity (RI) measured    spectrofluorimetrically for the samples taken from each of the    stages of the TSI: the inhaler device (R), stage 1 (1) and stage 2    (2). From those RI values, the percentage of active ingredient,    released from the capsule, that was present in each stage of the TSI    could be calculated for each of the unmilled samples A1 to A4 and    the milled samples B1 to B6.    -   Table 2 shows the mean percentage of active ingredient in each        stage, calculated for the six milled samples and the four        unmilled samples.    -   From the value of the mass of the capsule, the mass of the        Rotahaler, and the mass of the Rotahaler and capsule after the        powder had been expelled, the mass of powder lost from the        inhaler can be calculated. Thus the mass of the active        ingredient lost ran be calculated, assuming the mixture is        homogenous.    -   From the RI values for the standard solutions of salbutamol of        known concentration, the concentration of salbutamol and hence        the amount of salbutamol in each of stage 1 and stage 2 was        calculated for each capsule. This amount is expressed in Table 3        as the mean percentage lost from the inhaler for the milled and        unmilled samples.

TABLE 1 % of expelled salbutamol Sample R I (R, 1, 2) (R, 1, 2) B1 26.4,12.3, 19.2 36.24, 38.20, 25.55 B2 52.8, 5.7, 6.4 37.68, 14.27, 6.76 A126.3, 20.6, 9.8 30.97, 59.13, 9.89 B3 38.9, 9.2, 15.4 54.76, 25.90,19.33 A2 24.7, 20.3, 8.8 31.01, 60.53, 6.50 A3 46.5, 11.5, 6.3 61.41,32.71, 5.86 B4 13.8, 6.3, 9.3 39.59, 35.96, 24.45 B5 56.8, 3.1, 3.892.45, 4.54, 3.00 A4 19.6, 21.6, 8.0  22.4, 62.38, 15.23 B6 47.8, 7.3,9.1 69.31, 19.97, 10.73

TABLE 2 A (unmilled) B (milled) in the inhaler device 43.8 45.5 in stageone 53.7 32.8 in stage two 9.4 17.4

TABLE 3 A (unmilled) B (milled) in stage one 83.4 61.6 in stage two 16.638.4

The results show that there has been a significant increase in thedeposition Of the active particles in stage two of the apparatus for thelactose which has had the ball milling treatment. An increasedpercentage of active particles delivered to the second stage of the TSIcorresponds to increased deposition in the lower respiratory tract. Thusthe treatment has been successful and the surfaces of the lactosecarrier particles have been modified by the milling process such thatthe active particles adhere less strongly to the lactose carrierparticles.

EXAMPLE 2

Carrier particles were prepared by the following method. Meggle lactoseEP D30 (as described for Example 1 above) was used.

-   (a) The lactose was sieved by the following method to give samples    having particles with a range of diameter from 63 to 90 μm.    Successive samples of 50 g of lactose were sieved mechanically for    40 minutes using a stack of woven wire stainless steel sieves of    mesh diameters 63 μm, 90 μm, 125 μm, 180 μm and 250 μm. The sieving    process corresponded to that described in Example 1(a).

200 g samples of the lactose were taken from the particles that hadpassed through the 90 μm mesh sieve, but had remained on the 63 μmsieve. Those particles could be considered to have a diameter between 63μm and 90 μm.

-   (b) The samples obtained in step (a) above were milled in a    porcelain ball mill (manufactured by Pascal Engineering Company).    400 ml of plastics grinding balls having an approximate diameter of    20 mm were used and the mill was revolved at 6 revolutions per    minute for six hours.-   (c) Samples of the milled lactose particles obtained in step (b)    were mixed with active particles. 0.132 g of beclomethasone    dipropionate (BDP) (mass median diameter 1.13 μm) were added to    29.87 g of the milled lactose particles in a glass mortar. Each 30 g    of mixture was blended in the mortar using a glass pestle.    -   The blending process with 0.264 g of BDP was repeated for a        29.74 g sample of lactose particles having a diameter between 63        and 90 μm, but which had not been milled, to give a comparative        example.-   (d) After one day, several samples each of 25 mg of mixture were    taken from the container containing the unmilled particles and from    the container containing the milled particles. Each sample was used    to fill a respective one of size three capsules (size 3 transparent    capsules obtained from Davcaps of Hitchen, Herts., England). Those    capsules were allowed to stand for one day to allow the decay of any    accumulated electric charge.-   (e) The effect of the milling method on the surfaces of the lactose    particles was verified using a dry powder inhaler device and a    pharmacopoeial apparatus as described in steps (g) and (h) of    Example 1 above, the contents of the flasks containing the washing    from the stages of the TSI being assayed using High Performance    Liquid Chromotography (HPLC) analysis for the content of BDP and    compared against standard solutions containing 0.5 μg/ml and 1 g/ml    of BDP.    -   The percentage of BDP in each stage of TSI was calculated from        the standard response for each capsule and the mean for the        milled samples and the unmilled samples could be calculated.-   (f) Table 4 below shows the BDP content (in μg) recovered from each    stage of the TSI as an average for the samples of the milled and the    unmilled material. The respirable fraction (calculated as the    percentage of the total amount of drug emitted from the device, that    reaches stage two of the TSI) gives an indication of the proportion    of active particles which would reach the deep lung in a patient.    The numbers in brackets indicate the coefficient of variation for    each value.

TABLE 4 unmilled milled Device  31.8 (23.0) 19.3 (17.2) Stage 1 164.4(5.8) 78.6 (7.1) Stage 2  5.9 (14.2)  5.8 (15.9) Respirable Fraction (%) 3.5 (11.6)  6.9 (12.5)

The results show that there has been an increase in the deposition ofactive particles in Stage two of the TSI: indicating an increaseddeposition in the deep lung for the milled samples.

EXAMPLE 3

Carrier particles were prepared by the following method:

-   (a) Samples of 200 g Meggle lactose EP D30 were sieved mechanically    for 10 minutes using a single large (60 cm diameter) screen vibrated    on a rotary shaking device (William Boulton Ltd.). The lactose was    sieved first on a 125 μm mesh, then subsequently on 90 μm and    finally a 63 μm mesh to obtain the same size separation obtained in    step (a) of Example 2 above.-   (b) The samples obtained in step (a) above were milled in a    porcelain ball mill (Pascal Engineering company). 1200 ml of    plastics grinding balls having an approximate diameter of 20 mm were    used and the mill was revolved at 6 revolutions per minute for 24    hours.-   (c) Samples of the milled lactose particles obtained in step (b)    were mixed with active particles. 0.3182 g salbutamol sulphate (mass    median diameter 1.97 μm) were added to 29.68 g of the milled lactose    particles and mixed in a Turbula mixer (type TZC, WAB AG,    Switzerland) for 30 minutes.-   (d) After one day, several samples each of 25 mg of mixture were    taken from the container containing the milled carrier particles,    and several samples each of 25 mg were taken from the container    containing the unmilled carrier particles. Each sample was used to    fill a respective one of size three capsules (transparent capsules    obtained from Davcaps). Those capsules were allowed to stand for one    day to allow the decay of any accumulated electric charge.-   (e) The effect of the milling method on the surfaces of the lactose    particles was verified using a dry powder inhaler device and a    pharmacopoeial apparatus as described in steps (g) to (j) of Example    1 above, the contents of the flasks containing the washing from the    stages of the TSI being arranged using HPLC analysis as in Example    2.-   (f) Table 5 below shows the salbutamol content (in μg) recovered    from each stage of the TSI as an average for the samples of the    milled and the unmilled material. The respirable fraction (defined    in Example 2(f) above) was calculated. The numbers in brackets    indicate the coefficient of variation for each value.

TABLE 5 unmilled milled Device  32.4 (5.3)  61.3 (8.8) Stage 1 144.1(5.1) 116.6 (10.7) Stage 2  12.2 (14.3)  25.2 (10.2) Respirable Fraction(%)  7.8 (10.8)  17.9 (14.1)

The results show that there has been an increase in the deposition ofactive particles in stage two of the TSI, indicating an increaseddeposition in the lower lung, for the milled samples.

EXAMPLE 4

Carrier particles were prepared by the following method.

-   (a) 50 g samples of milled and unmilled Meggle lactose EP D30    particles were prepared as described in steps (a) and (b) in Example    2 except that the mill was operated at 60 rpm for 6 hours using 90    to 125 μm lactose starting material.-   (b) 200 g samples of Meggle lactose EP D30 particles re milled in a    porcelain ball mill using plastics grinding balls. The mill was    revolved at 60 rpm for 24 hours. The milling fractured the lactose    particles. Agglomerates of fine lactose particles having particle    size in the range of from 0.5 to 90 μm were produced, the median    diameter being 24 μm.-   (c) 2 g of particles produced in step (b) were mixed with 18 g of    milled particles produced in step (a).-   (d) The process described in Example 2(c) and (d) was carried out    for the milled and treated and the unmilled lactose samples.-   (e) The effect of the treatment method on the surfaces of the    lactose particles was verified as described in steps (g) and (h) of    Example 1 except that the samples were assayed for drug content    using HPLC analysis as in Example 2.-   (f) The respirable fraction calculated in respect of the treated    sample was 25.5%.

The invention claimed is:
 1. A method of producing particles for use ascarrier particles in dry powder inhalers, the method comprising thesteps of: selecting particles of a pharmacologically inert material orcombination of materials, to obtain carrier particles having a diameterof between 50 μm and 1000 μm; milling the selected carrier particles todislodge small grains from the surfaces of the selected particleswithout substantially changing the size of the selected carrierparticles, wherein the step of selecting the size of the carrierparticles occurs prior to the step of milling the selected particles;wherein the milling step is performed in a recirculated low fluid energymill, and wherein the small grains become reattached to the surfaces ofthe carrier particles.
 2. A method according to claim 1 wherein theparticles are crystalline sugar particles.
 3. A method according toclaim 1 wherein the particles are lactose particles.
 4. A method ofproducing a dry powder for use in dry powder inhalers, the methodincluding producing carrier particles using a method according to claim1, and mixing the carrier particles with active particles such that theactive particles adhere to the surfaces of carrier particles.
 5. Amethod according to claim 4 wherein the diameter of the active particlesis between 0.1 μm and 3 μm.
 6. A method according to claim 4 wherein thecarrier particles and the active particles are mixed in a container madefrom a plastics material.
 7. A method according to claim 4 wherein thecarrier particles and the active particles are mixed for at least fiveminutes.
 8. A method according to claim 7 wherein the carrier particlesand the active particles are mixed for thirty minutes.
 9. A methodaccording to claim 7 wherein the mixing is interrupted and the mixtureof carrier particles and active particles is sieved.
 10. A methodaccording to claim 9 wherein sieve mesh size is about 250 μm.
 11. Amethod according to claim 4 wherein the carrier particles and the activeparticles are mixed in a ratio by weight of 125 to
 1. 12. A methodaccording to claim 4 wherein the active particles include a β₂-agonist.13. A method according to claim 12 wherein the active particles includeterbutaline, a salt of terbutaline or a combination thereof.
 14. Amethod according to claim 12 wherein the active particles includesalbutamol, a salt of salbutamol or a combination thereof.
 15. A methodaccording to claim 14 wherein the active particles include salbutamolsulphate.
 16. A method as claimed in claim 4, wherein the small grainsbecome reattached to the surface of the carrier particles.
 17. A methodas claimed in claim 1, wherein the small grains become reattached to thesurface of the carrier particles in a mixing step that follows themilling step.
 18. A method according to claim 3, wherein diameter of theselected particles is less than 355 μm.
 19. A method according to claim3, wherein diameter of the selected particles lies between 60 μm and 250μm.
 20. A method according to claim 3, wherein diameter of the selectedparticles lies between 90 μm and 250 μm.